Glucocorticoids circulate in the blood in an active form (i.e., cortisol in humans) and an inactive form (i.e., cortisone in humans). Many studies have shown that 11β-HSD1 functions primarily as a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone), and thereby amplifies glucocorticoid action in a tissue-specific manner leading to higher local concentration of cortisol Inhibition of 11β-HSD1 prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects.
11β-HSD1 is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate) as cofactors. 11β-HSD1 is widely expressed in various tissues such as liver, bone, brain, lung, adipose, and vascular smooth muscle cells.
Excessive glucocorticoid action in liver and adipose tissues leads to insulin resistance, type 2 diabetes, dyslipidemia, increased abdominal obesity, and hypertension (Su et al., Progress in Medicinal Chemistry, 46, 29-130 (2008); Webster et al., Expert Opin. Ther. Patents, 17 (12), 1407-1422 (2007); Wang, Drug Discovery Today: Ther. Strategies, 4(2), 117-122 (2007); Link, Current Opin. In Invest. Drugs, 4 (4), 421-429 (2003); Seckl et al., Endocrinology, 142, 1371-1376 (2001) and references cited therein). Accordingly, the 11-β HSD1 inhibitor class has been recognized as one of the highly promising therapeutic classes (Norman P., Insight Pharma Reports, 103-110 (April 2007)).
Published data indicates that elevated levels of glucocorticoids in mammalian brain may cause neuronal degeneration and dysfunction, particularly in the aged (de Quervain et al., Hum Mol. Genet., 13, 47-52 (2004); Belanoff et al. J. Psychiatr Res., 35, 127-35, (2001)). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging. (Issa et al., J. Neurosci., 10, 3247-3254 (1990); Lupien et al., Nat. Neurosci., 1, 69-73 (1998); Yau et al., Neuroscience, 66, 571-581 (1995)). Chronic excessive cortisol levels in the brain may result in neuronal loss and neuronal dysfunction. (Kerr et al., Psychobiology, 22, 123-133 (1994); Woolley, Brain Res., 531, 225-231, (1990); Landfield, Science, 272, 1249-1251 (1996)).
Furthermore, glucocorticoid-induced acute psychosis exemplifies a more pharmacological induction of this response, and is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et al., Ann NY Acad. Sci., 1032, 191-194 (2004)). It has been recently shown that 11β-HSD1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the non-selective 11β-HSD1 and 11β-HSD2 inhibitor carbenoxolone improved verbal fluency and memory (Thekkapat et al., Proc Natl Acad Sci USA, 101, 6743-6749 (2004)). Excessive glucocorticoid levels also affects psychopathology, as shown in animal models, it leads to increased anxiety and aggression. Chronic elevation of cortisol has been also associated with depression in Cushing's disease (McEwen, Metab. Clin. & Exp., 54, 20-23 (2005)). A number of animal and clinical studies have provided evidence for the correlation between increases in glucocorticoid levels and neuropsychiatric disorders such as major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, and depression in Cushing's syndrome (Budziszewska, Polish J. of Pharmacol., 54, 343-349, (2002); Ströhle et al., Pharmacopsychiatry, 36, S207-S214 (2003); DeBattista et al., TRENDS in Endocr. Metab., 17, 117-120 (2006); Norman et al., Expert Rev. Neurotherapeutics, 7, 203-213 (2007)).
Thus, inhibiting 11β-HSD1 benefits patients suffering from non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, central nervous system disorders, age-related or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's disease and associated dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, treatment resistant depression, and other diseases and conditions mediated by excessive glucocorticoid action.